Project Summary/Abstract Regioselective C-H functionalization of biologically relevant molecules, including medicinal candidates and biochemical probes, enables access to targeted analogs with potentially improved biomedical value. A strategy that employs radical relay mechanisms to invent pharmacologically valuable C-H functionalization methods is proposed. The key innovation in this approach is the design and use of radical precursor tethers that may serve as temporary chaperones to effect targeted manipulation of C-H bonds. These tethers allow the application of robust, regioselective 1,5 hydrogen atom transfer (HAT) mechanisms for the manipulation of varying positions in a molecule. As a proof of concept, ? and ? C-H functionalizations of alcohols are proposed, since these are ubiquitous motifs in organic chemistry, and also because such synthetic transformations are both valuable and challenging to perform using known methods. The independent research goals include: Goal 1: To develop a tethered radical relay strategy for the ? C-H amination of alcohols. Direct conversion of alcohols to their biologically valuable ?-amino analogs via C-H amination will be pursued via three parallel design strategies with tethered amine-containing, radical precursors. Goal 2: To develop a tethered radical relay strategy for alcohol ? C-H functionalizations. Interrupted Barton reactions may also be harnessed within this tether strategy to enable the invention of valuable C-H functionalization methods, such as ? C-H deuteration, fluorination, oxygenation, and alkylation. Goal 3: To develop a catalytic, radical relay strategy to enable ? C-H functionalizations. Iron-catalyzed initiation and interruption of the Barton reaction will facilitate the invention of unprecedented functionalizations of remote C-H bonds, such as ? C-H deuteration, arylation, and methylation. Importantly, tandem development of the directing group tethers (for ? C-H functionalizations), as well as the iron-catalyzed radical trapping protocols (for ? C-H functionalizations), will enable the combination of both strategies for the invention of further biologically useful, synthetic methods. Furthermore, the future extension of this strategy to catalytic tethers of varying sizes will allow for the functionalization of other unbiased C-H positions (?, ?, ?, ?, ? to alcohols, acids, or amines). Notably, regioselectivity in each of these cases will depend on the length of the tether, rather than substrate-biased selectivity. Ultimately, the value and significance of this chaperone-mediated, radical relay strategy for targeted C-H functionalization will be demonstrated via manipulation of the anti-cancer drug, paclitaxel. The synthetically challenging modification of the C6 position, which is coincidentally the site most prone to in vivo metabolism, will be accomplished by the proposed ? C-H functionalizations of the C7 alcohol. The targeted introduction of pharmacologically valuable groups to block metabolism or enhance tubulin binding will showcase the value of this strategy in enabling post-synthetic modifications of drug candidates to rapidly access potentially improved medicines.